Disorders related to increased glucose levels generally refer to a disease process derived from multiple causative factors and characterized, inter alia, by elevated levels of plasma glucose (i.e., hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test.
Hyperglycemia can be treated with a variety of therapeutic agents for example, peroxisome proliferator-activated receptor active agents, biguanides, alpha-glucosidase inhibitors, and insulin sensitizers. DPP-IV inhibitors have been found to be useful in the treatment of disorders related to increased glucose level, and particularly hyperglycemia. See, for example, PCT application Publications Nos. WO 97/40832 and WO 98/19998, and U.S. Pat. Nos. 5,939,560, and 6,699,871. The usefulness of DPP-IV inhibitors in the treatment of hyperglycemia is believed to be based on the understanding that DPP-IV in vivo inactivates glucagon-like peptide 1 (“GLP-1”) and gastric inhibitory peptide (“GIP”). GLP-1 and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin. Inhibition of DPP-IV is believed to lead to decreased inactivation of the incretins, and this in turn results in increased effectiveness of incretins in stimulating production of insulin by the pancreas. DPP-IV inhibition is believed to lead to an increased level of serum insulin.
Two of the DPP-IV inhibitors have been approved by the United States FDA, i.e., sitagliptin (JANUVIA® marketed by Merck and Co.) and saxagliptin (ONGLYZA® marketed by Bristol Myers Squibb). Another DPP-IV inhibitor, vildagliptin (GALVUS® marketed by Novartis) is currently commercially available in Europe.
There is a continuing need for new compositions for the treatment of disorders related to increased glucose level and other disorders implicating DPP-IV.